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PAHSAs enhance hepatic and systemic insulin sensitivity through direct and indirect mechanisms
Peng Zhou, … , Dionicio Siegel, Barbara B. Kahn
Peng Zhou, … , Dionicio Siegel, Barbara B. Kahn
Published August 26, 2019
Citation Information: J Clin Invest. 2019;129(10):4138-4150. https://doi.org/10.1172/JCI127092.
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Research Article Endocrinology Metabolism

PAHSAs enhance hepatic and systemic insulin sensitivity through direct and indirect mechanisms

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Abstract

Palmitic acid esters of hydroxy stearic acids (PAHSAs) are bioactive lipids with antiinflammatory and antidiabetic effects. PAHSAs reduce ambient glycemia and improve glucose tolerance and insulin sensitivity in insulin-resistant aged chow- and high-fat diet–fed (HFD-fed) mice. Here, we aimed to determine the mechanisms by which PAHSAs improve insulin sensitivity. Both acute and chronic PAHSA treatment enhanced the action of insulin to suppress endogenous glucose production (EGP) in chow- and HFD-fed mice. Moreover, chronic PAHSA treatment augmented insulin-stimulated glucose uptake in glycolytic muscle and heart in HFD-fed mice. The mechanisms by which PAHSAs enhanced hepatic insulin sensitivity included direct and indirect actions involving intertissue communication between adipose tissue and liver. PAHSAs inhibited lipolysis directly in WAT explants and enhanced the action of insulin to suppress lipolysis during the clamp in vivo. Preventing the reduction of free fatty acids during the clamp with Intralipid infusion reduced PAHSAs’ effects on EGP in HFD-fed mice but not in chow-fed mice. Direct hepatic actions of PAHSAs may also be important, as PAHSAs inhibited basal and glucagon-stimulated EGP directly in isolated hepatocytes through a cAMP-dependent pathway involving Gαi protein–coupled receptors. Thus, this study advances our understanding of PAHSA biology and the physiologic mechanisms by which PAHSAs exert beneficial metabolic effects.

Authors

Peng Zhou, Anna Santoro, Odile D. Peroni, Andrew T. Nelson, Alan Saghatelian, Dionicio Siegel, Barbara B. Kahn

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Figure 5

PAHSAs directly inhibit basal and glucagon-stimulated EGP in isolated hepatocytes through a cAMP-dependent pathway involving Gαi protein–coupled receptors.

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PAHSAs directly inhibit basal and glucagon-stimulated EGP in isolated he...
Hepatic glucose production (HGP) in murine primary hepatocytes treated with DMSO (0.2%; white bars), 9-PAHSA, and/or insulin (A). n = 4 wells/condition. HGP in hepatocytes treated with DMSO (0.2%), glucagon, and 9-PAHSA + glucagon (B). n = 4–8 wells/condition. (C) cAMP levels were measured 30 minutes after glucagon or 9-PAHSA + glucagon treatment. n = 12–18 wells/condition. (D) HGP in primary hepatocytes treated with DMSO (0.2%) (white bar), 8-bromo-cAMP (8-Bro-cAMP), or 9-PAHSA + 8-bromo-cAMP. n = 5–9. (E) HGP in primary hepatocytes treated with DMSO (0.2%) (white bars), insulin, 9-PAHSA, pertussis toxin (PTX), or 9-PAHSA + PTX (left); HGP in primary hepatocytes treated with DMSO (0.2%), glucagon, 9-PAHSA, PTX, or glucagon + 9-PAHSA + PTX (right). n = 7–14 wells/condition. For A–E, glucose output was measured 3 hours after treatment. *P < 0.05 versus vehicle-treated control cells (first bar), §P < 0.05 versus vehicle- (fifth bar) or insulin-treated cells, ‡P < 0.05 versus glucagon, †P < 0.05 versus 9-PAHSA alone, and ##P < 0.05 versus 9-PAHSA + glucagon. Statistical significance for all panels was evaluated by ANOVA followed by Tukey’s post hoc tests or unpaired 2-tailed Student’s t test. Data are mean ± SEM. (F) Model of the signaling pathway mediating PAHSAs’ effects on HGP. In hepatocytes, glucagon increases EGP through the adenylyl cyclase/PKA/CREB pathway, whereas PAHSAs activate a Gαi GPCR (GαiPCR), inhibiting adenylyl cyclase, which decreases cAMP levels, reducing PKA activity. As a result, phosphorylation of CREB, a PKA protein target, is decreased, resulting in reduced expression of G6pc1 and Pck1, 2 CREB target genes. In addition, cAMP reduction by PAHSAs inhibits G6pase activity. The inhibition of these cAMP target proteins leads to reduced HGP by PAHSAs. Black arrows, effect of glucagon on PKA signaling pathway; gray arrows, effects of PAHSAs. CRE, cAMP response elements; G6P, glucose-6-phosphate; Glut2, facilitated diffusion glucose transporter 2.
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